在一个中国家庭中,GAS2的一个新变体与常染色体显性非综合征性听力障碍有关。

IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Human Genomics Pub Date : 2024-07-02 DOI:10.1186/s40246-024-00628-2
Luping Zhang, Danya Zheng, Lian Xu, Han Wang, Shuqiang Zhang, Jianhua Shi, Nana Jin
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引用次数: 0

摘要

基因敲除 GAS2(生长停滞特异性蛋白 2)会导致耳蜗导管支持细胞中微管束的混乱和不稳定,从而导致体内听力损失。然而,GAS2 变体导致听力损失的分子机制仍然未知。通过全外显子组测序,我们在一个大型显性家族中发现了 GAS2 的一个新的杂合剪接变异(c.616-2 A > G),它是与晚发性和进行性非综合征性听力损失(NSHL)分离的唯一候选突变。这种剪接突变导致内含子保留,并产生 C 端截短蛋白(命名为 GAS2mu)。从机理上讲,GAS2mu 通过泛素-蛋白酶体途径的降解作用增强,表达 GAS2mu 的细胞表现出微管束紊乱。此外,GAS2mu 还通过增加 Bcl-xS/Bcl-xL 的比例进一步促进细胞凋亡,而不是像野生型 GAS2 那样通过 p53 依赖性途径,这表明 GAS2mu 是一种加剧细胞凋亡的毒性分子。我们的研究结果表明,GAS2 的这种新型变体会促进自身蛋白降解、微管紊乱和细胞凋亡,从而导致携带者听力损失。这项研究扩大了GAS2变体的范围,阐明了其潜在的致病机制,为今后研究新的治疗策略以预防GAS2相关的渐进性听力损失奠定了基础。
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A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family.

Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616-2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss.

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来源期刊
Human Genomics
Human Genomics GENETICS & HEREDITY-
CiteScore
6.00
自引率
2.20%
发文量
55
审稿时长
11 weeks
期刊介绍: Human Genomics is a peer-reviewed, open access, online journal that focuses on the application of genomic analysis in all aspects of human health and disease, as well as genomic analysis of drug efficacy and safety, and comparative genomics. Topics covered by the journal include, but are not limited to: pharmacogenomics, genome-wide association studies, genome-wide sequencing, exome sequencing, next-generation deep-sequencing, functional genomics, epigenomics, translational genomics, expression profiling, proteomics, bioinformatics, animal models, statistical genetics, genetic epidemiology, human population genetics and comparative genomics.
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